Brain Pathology Case of the Month - January 2020


FINAL DIAGNOSIS

  1. First, second, and fourth resection: Posterior ossa Ependymoma (WHO grade III; Methylation subgroup A)
  2. Malignant glioma, corresponding to glioblastoma (WHO grade IV), most likely radiation induced

DISCUSSION

Malignant pediatric brain tumors represent a very heterogeneous group with a great variability in the age of onset, localization, disease course and long-term outcome as well as radiological, histological and molecular features. This makes clinical treatment complicated and still leaves patients with high mortality rates. Previously, these tumors have been classified according to distinct histomorphological features and localization. However, considerable effort has recently been made towards the molecular characterization of brain tumors, revealing that morphologically similar appearing tumors may belong to entirely different molecular entities with different biological behavior and clinical outcome (1, 2). Thus, definite diagnosis and classification of pediatric brain tumors based on histology alone is in many cases not possible and requires further molecular analyses.

In the case presented here, an initial diagnosis of medulloblastoma (WHO grade IV) was made by several neuropathologists and seemed to be obvious given the undifferentiated small blue round cell appearance (Figure 1A) along with the infratentorial localization. However, one year later, another resection specimen from the same localization was referred for histological examination, which exhibited none of the previously observed embryonal features, but rather formations of perivascular pseudo-rosettes (Figure 1B) so that ependymoma (WHO grade II) was diagnosed.

Because of this unusual combination, 450K-methylation analysis was performed on the two tumor samples. In both cases the highest classifier scores were achieved for posterior fossa ependymomas, group A (EPN_PFA) (0.67 (1) and 0.99 (2), respectively), which depict a class of ependymomas with an aggressive behavior and bad outcome, requiring intensive therapy and monitoring (2). Although the CNVs of both tumor samples appear quite different on a first glance, the identical changes on chromosome 22, indicate that they represent both subclones of the same tumor (Figs. 1A, 1B). Therefore, the 450K-methylation profiling strongly suggests that the initial manifestation represented like the second one an anaplastic ependymoma and not a medulloblastoma, thus prompting to consider methylation profiling for all pediatric small blue round cell tumors on a regular basis. An explanation for the different CNVs might be that the cell-dense, malignant parts of the tumor were successfully hit by the aggressive radiation and chemotherapy, giving way for lower malignant subclones that are less susceptible to radiation and chemotherapeutic drugs.

13 years later, the patient presented again with an infratentorial mass, which histologically met the criteria for glioblastoma (WHO grade IV) and only few months after that, a spinal tumor was resected and histologically diagnosed as ependymoma. While for the spinal tumor highest classifier scores were again reached for the group of EPN_PFA (0.77), methylation analysis of the infratentorial mass revealed only low classifier scores (0.5) for the methylation class family glioblastoma, IDH wildtype, indicating that this tumor was distinct from the first, second, and fourth tumor manifestation and hence not a recurrence of the initial tumor, but a secondary tumor. Additionally, while the CNV profile of the spinal tumor exhibited remarkable similarities to the first two tumors (Fig. 1D), the CNV profile of the infratentorial tumor was entirely different from the three other tumors (Fig. 1C). Interestingly, in a t-distributed stochastic neighbor embedding (t-SNE) representation (3), this tumor was arranged with the group of H3 K27M mutant diffuse midline gliomas (DMG_K27) (Fig. 1E), although this association was not found by the DNA methylation classifier and no mutations of H3F3A, HIST1H3B, or HIST1H3C, but loss of trimethylation of Histone H3 at position K27 were observed. However, as t-SNE primarily indicates a high level of similarity between the tumor described here and DMG_K27M and as DNA methylation classifier and t-SNE are fundamentally different approaches, this observation is not necessarily conflicting. As expected, the other three tumors clustered within the group of EPN_PFA.

Given the history of radiation therapy, a causal relationship between irradiation and the secondary tumor seems likely and the classic criteria for radiation induced malignancies (i. e. irradiated region, sufficient latency, distinct histology from the original tumor, and no genetic predisposition for tumor development were met (4). Radiation induced gliomas (RIG) are a relatively rare long-term complication of radiation therapy that occur with an average latency of 5-10 years after irradiation (5, 6). Although they resemble their sporadically arising counterparts histologically, not much is known about their molecular characteristics. One recent study analyzed four RIGs and found that at least in these cases the classically detected genetic aberrations, such as IDH, H3, BRAF, or TERT promotor mutations were not present, indicating that different genetic alterations might play a role in the development of RIGs (7). Further studies are needed to closer characterize the molecular profiles of RIGs, also with regard to specialized treatment of RIGs.

Still, this case emphasizes the relevance and importance of molecular analyses of pediatric brain tumors as (1) histological assessment only can be misleading, particularly in small blue round cell tumors and (2) different tumor entities in the same patient can be clearly distinguished.

ACKNOWLEDGEMENTS

U.S. is supported by the Fördergemeinschaft Kinderkrebs-Zentrum Hamburg.

REFERENCES

  1. Sturm, D, Orr, B A, Toprak, U H, Hovestadt, V, Jones, D T W, Capper, D, Sill, M, Buchhalter, I, et al (2016) New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell. 164(5): 1060-1072.
  2. Pajtler, K W, Witt, H, Sill, M, Jones, D T, Hovestadt, V, Kratochwil, F, Wani, K, Tatevossian, R, et al (2015) Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell. 27(5): 728-43.
  3. van der Maaten, L, and Hinton, G. (2008) Visualizing data using t-sne. J Machine Learning Res. 9: 2579-2605.
  4. Cahan, W G, Woodard, H Q, et al. (1948) Sarcoma arising in irradiated bone; report of 11 cases. Cancer. 1(1): 3-29.
  5. Prasad, G, Haas-Kogan, D A (2009) Radiation-induced gliomas. Expert Rev Neurotherap. 9(10): 1511-7.
  6. Lee, J W, Wernicke, A G (2016) Risk and survival outcomes of radiation-induced CNS tumors. J Neurooncol. 129(1): 15-22.
  7. Nakao, T, Sasagawa, Y, Nobusawa, S, Takabatake, Y, Sabit, H, Kinoshita, M, Miyashita, K, Hayashi, Y, Yokoo, H, Nakada, M (2017) Radiation-induced gliomas: a report of four cases and analysis of molecular biomarkers. Brain Tumor Pathol. 34(4): 149-154.

Contributed by Viktoria C. Ruf, MD, Anne Schöler, PhD, David Capper, MD, Thomas Arzberger, MD, Jochen Herms, MD, and Ulrich Schüller, MD5


International Society of Neuropathology